In vivo and in vitro studies suggest that HMGCoA reductase inhibitors, or statins, may have a number of antitumor activities. They have been found to arrest cell cycle progression, induce apoptosis, and suppress angiogenesis and inflammation. The relation between chronic use of statins and the risk of lymphoid malignancies in humans has not been well characterized and the limited epidemiologic evidence to date is conflicting. The overall objective of this application is to examine the association between use of statins and risk of a lymphoma and whether this association is modified by the presence of conditions related to a higher risk of lymphoma. We will achieve our objective by pursuing two specific aims: 1) To quantify the association between statin use and risk of lymphoma, overall and by lymphoma subtypes; and 2) To assess the association of lymphoma risk with statin use among persons at high risk for lymphoma. The study will be a nested case-control study conducted within 6 health systems in the Cancer Research Network (CRN), with a total population of over 8 million members. Incident diagnoses of lymphoid malignancies (n~ 18,000) will be identified from population-based health system cancer registries. Five controls will be matched to each case on, age, sex, health system, and duration of membership. Statin and other medication use will be obtained from comprehensive electronic pharmacy records. The proposed study will include the largest study population and have the most detailed pharmacy data to address this research question to date. Conditional logistic regression analysis will be used to address aim 1; statin users will be compared both to non-users and to users of other antilipemics (i.e., anion exchange resins, fibrates, nicotinic acid, and ezetimibe). The working hypothesis is that use of statins overall will be associated with a reduced risk of lymphoma while use of other antilipemics will not, and that the association will be stronger for lipophilic statins (i.e., lovastatin, simvastatin, and atorvastatin) and for lymphoma subtypes most strongly related to chronic inflammation (i.e., diffuse large B cell lymphoma). Under the second aim, the working hypothesis is that statins will show a stronger protective effect against lymphoma among subjects affected by autoimmune conditions related to higher risk of lymphoma (i.e., rheumatoid arthritis, systemic lupus erythematosus, and Sjvgren's syndrome). The proposed research is significant given the high and expanding prevalence of statin use in the US and the need to identify and quantify any secondary risks and benefits of these widely used drugs. Significance. Lymphomas are a group of malignancies whose etiology remains poorly understood and for which few risk factors have been identified. Therefore, limited preventive measures are available. The confirmation that statins protect against the development of lymphoma will provide enormous scientific and public health impact and significance in the general population. An additional examination that will be included in this study (Aim 2) could lead to effective chemoprevention strategies for persons at high risk for lymphoma. Like most systemic agents, statins are not risk-free. However, statins are widely used, and the risk of serious adverse events is relatively low given the exposure prevalence. To provide thorough evaluation, the risks related to statin exposure will be evaluated in this study in addition to the benefits. Investigators. This study includes experienced investigators as well as early stage investigators. In collaboration with experienced investigators, an early stage investigator (Dr. Chun Chao) will lead evaluation of statins and lymphoma in a high-risk population (Aim 2). Novelty/Approach/Environment. This study will build upon existing resources to evaluate the benefit (and risk) of statins on risk for lymphoma. Therefore, this study will provide cost- and time-efficient results that will address this important public health issue. PUBLIC HEALTH RELEVANCE: Lymphomas are a group of malignancies whose etiology remains poorly understood and for which few risk factors have been identified. Therefore, limited preventive measures are available. The confirmation that statins protect against the development of lymphoma will provide enormous scientific and public health impact and significance in the general population, and will provide chemoprevention strategies for persons at high risk for lymphoma.